Abstract A76: MicroRNA mediated negative regulation of caveolin 1 as a biological mechanism driving breast cancer disparities

Abstract

Abstract Although rates of breast cancer incidence are lower in African American (AA) women, the mortality rates are significantly higher compared to non-Hispanic white (WNH) women. This shocking statistic illustrates the racial disparities in breast cancer, as AA women have a poorer prognosis compared to WNH women. While this may be due in part to socioeconomic and standard of care issues, increasing evidence suggests that the racial disparity exists independent of these issues and could also be attributed to poorly understood inherent genetic and molecular characteristics within racial specific tumors. Caveolin-1 (Cav1) is a scaffolding protein with a tumor suppressor role. Loss of Cav1 in the tumor stromal compartment has emerged as a novel biomarker for predicting poor clinical outcome in all of the most common subtypes of human breast cancer, including the more lethal triple negative subtype which is significantly more common in AA women. While the loss of stromal Cav1 is becoming well established as a marker of poor outcome in breast cancer, the mechanism of this loss is still unknown. We propose that differences in microRNA mediated stromal Cav1 loss between AA and WNH women is driving the racial disparity in breast cancer. MicroRNAs (miRNAs) are short, endogenous, non-coding RNA that function as negative regulators of gene expression. miR-510 is an oncogenic miRNA that has been shown to be elevated in breast tumors. Cav1 is a predicted target of miR-510 and therefore miR-510 mediated negative regulation may be a novel mechanism of Cav1 loss in the tumor stroma. Our research shows that Cav1 is directly targeted by miR-510 by luciferase reporter assay and that overexpression of miR-510 leads to downregulation of Cav1 protein expression, specifically in the stromal compartment. Tumor epithelium and stroma co-culture assays demonstrate that epithelial derived miR-510 may be transferred to neighboring stromal cells and negatively regulate Cav1 expression in the stromal compartment. This may be racially significant as our supporting studies also show that miR-510 levels are elevated and Cav1 levels are reduced in AA breast cancer patients compared to their white counterparts. Our results suggest that the difference in miR-510 mediated regulation of stromal Cav1 is driving racial disparity in breast cancer. Citation Format: Qi Jin Guo, Brooke King, Bobbie Blake, Amanda C. LaRue, Judith D. Salley, Marvella E. Ford, Ashley Evans-Knowell, Victoria J. Findlay. MicroRNA mediated negative regulation of caveolin 1 as a biological mechanism driving breast cancer disparities. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr A76.